Process for the production of 2-acylimidazoles

ABSTRACT

THE INVENTION RELATES TO 2-ACYL-1-ALKYL- OR -ARYL-IMIDAZOLES, WHEREIN THE 4- AND 5-POSITIONS OF THE IMIDAZOLE RING AS WELL AS THE 1-ALKYL OR -ARYL SUBSTITUTENT MAY BE SUBSTITUTED, WHICH, IN THE FORM OF THEIR ACID ADDITION SALTS, POSSES FUNGICIDAL ACTIVITY, AND WHICH ARE ALSO USEFUL AS INTERMEDIATES IN FURTHER SYNTHESES. THE INVENTION ALSO PROVIDES A PROCESS FOR PRODUCING SUCH COMPOUNDS BY ACYLATION OF THE CORRESPONDING IMIDAZOLE, UNSUBSTITUTED IN THE 2-POSITION, WITH THE APPROPRIATE ACID HALIDE.

Patented Nov. 13, 1973 W P t 01 ac 4 Claims ABSTRACT on THE DISCLOSURE The invention relates to 2-acyl-1-alkylor aryl-imidazoles,'- wherein the 4--and 5-positions of the imidazole ring as well as the-1-alky1'or aryl substituent may be substituted, which, in the form of their acid addition salts, possess fungicidal activity, and which are also useful as intermediates in further syntheses. The invention also provides a process for producing such compounds by acylation of the corresponding imidazole, unsubstituted in the 2-position, with the appropriate acid halide.

The present invention relates to 2-acyl-l-alkylor arylimidazoles which, in the form of their acid addition salts, possess fungicidal activity and to a process for their "preparation. 1 It'is knowntl'iatimidazole k'etones in general are very difficulttdhbtaih, since imidazoles cannot be subjected to aflFriedel crafts synthesis (see K. Hofmann: The Chemistry' of- Heter ocyclic Compounds 1953). Thus, 2-benzoylimidazoleis prepared by subjecting 2-benzylimidazole to a chromic acid oxidation (see Chem. Ber. 66, 1900 (1933):). Han attemptis made to acylate imidazoles 1 with acylating agents, the hydrogen atom at the nitrogen is first replaced. In addition, however, .various by-products are formed by side reactions whose mechanism is not clear. It is accordingly an object of the present invention to provide certain novel" imidazole ketones, i.e. acylimidazoles, and 'to provide newprocesses for their preparation. In accordance with the invention there are provided acylimidazoles of the formula X' N u n 15, r'v (I) in which is tertiary alkyl; halo-, nitroor amino-alkyl; alkoxy;

alkylt-hio; aryloxy; arylthio; dialkylamino; or phenyl, biphenyl, naphthyl,;cycloalkyl, cycloalkenyl, pyridyl, pyrazolyl,. oxazolyl, thiadiazolyl, furyl or thienyl, optionally=substituted by one or more halo-, nitro-, amino-, =alkoxy-, hydroxy-or alkyl groups, or

the radical ofthe formula p W T stitut'edby one or-more halogen, nitro or alkyl groups,

or a"cy'ano radical, X and Y are each independently hydrogen, halogen, alkyl, haloalkyl, phenylor haloph'enyl or X and Y together e5" v v As: typical examples of compounds of the formula ;(IV already known :in the art, there are listed: car- --bonic acid dichloride, oxalyl dichloride, trifluoroacetyl chloride, trichloroacetyl chloride, tert. butyryl chloride, .chloroformic acid ethyl ester, chloroformic acid phenyl -'ester,. chlorothioformic acid S-ethyl ester, dimethylcarwith the CH=CH-"group -standing between them are a benzene ring.'-

The invention also provides a process for the product1on of a compound of Formula I in which in the presence of a strongly polar diluent and a strong base, an imidazole of the formula i R (III) is reacted with a compound of the formula R"-CO-Z (IV) in which X, Y and R have the meanings set forth hereinabove,

R is halogen, halocarbonyl, halocarbonylmethyl or halocarbonylphenyl, or has the same meaning as R in Formula I and Z is halogen.

Illa IV ZU-CO-Q In the several foregoing formulae, desirably R is a tertiary alkyl radical with 4-6 carbon atoms, or a chloro-, fluoro-, bromo-, nitroor amino-alkyl radical with 1-6 carbon atoms; or lower alkoxy, lower alkylthio or dilower alkylamino radical preferably with 1-4 carbon atoms in each alkyl group; or a phenoxy or phenylthio radical; or a phenyl, biphenyl, naphthyl, cycloalkyl or cycloalkenyl with 5 or 6 carbon atoms, pyridyl, pyrazolyl, oxazolyl, thiadiazolyl or furyl radical optionally substituted by one or more chlorine, fluorine, bromine, nitro, amino, lower alkyl or alkoxy preferably with 1-4 carbon atoms, or hydroxy groups; or a group of Formula II; R is an alkyl radical with l-6 carbon atoms, cyano, or a phenyl or benzyl radical which may be substituted by chlorine, nitro or methyl; X and Y are hydrogen, chlorine, fluorine, bromine, or lower alkyl preferably having l-4 carbon atoms, or phenyl radical which may be substituted by chlorine, fluorine or bromine,.or X and'Y together with the CH=CH group standing between them are a benzene ring.

Preferably, also, Z is chlorine or the radical R 'co o V l p in which R hasthe same meaning as in the: last paragraph above. I I

bamoyl. chloride,: benzoyl chloride, p-chlorobenzoyl chloride, o-fiuorobenzoyl chloride, chlorothioformicacid S- phenyl ester, benzoyl chloride, p-chlorobenzoyl chloride, o-fluorobenzoyl chloride, m-bromobenzoyl chloride, piodobenzoyl chloride, 3,5-dichlorobenzoyl chloride, 4- nitrobenzoyl chloride, o-methoxybenzoyl chloride, dimethylanthranyl chloride hydrochloride, l-naphthylcarboxyhc acid chloride, 4-pyridinecarboxylic acid chloride hydrochloride, Z-furylcarboxylic acid chloride, 2-thienylcarboxylic acid chloride, 2-chloro-6-methyl-pyridyl-4-carboxylic acid chloride, phthalyl dichloride, 1,5-dimethylpyrazolyl-3-carboxylic acid chloride, 3,4-dichlorofuryl-2- carboxylic acid chloride, and the like.

The imidazole suitable for carrying out the reaction according to the invention are clearly defined by the Formula III mentioned above, and are known in the art. As examples of the imidazoles to be used, there are listed: N-methylimidazole, N-phenylimidazole, N-benzylimidazole, N-rnethyl-4,S-dichloroimidazole, N-cyanoimidazole; further, N-p-chlorophenylimidazole, N-3,4-dichlorophenylimidazole, N 4 chlorobenzylimidazole, N-2,4-dinitrophenylimidazole, N-2-methyl-4,6-dinitrophenylimidazole.

The reaction according to the invention must be carried out in the presence of at least one strongly polar diluent. By strongly polar diluents there are meant, for the purposes of the present invention, inert organic solvents which have a dielectric constant of at least 4.8 (chloroform), preferably of at least 20.7 (acetone). These solvents include amides, such as dimethyl formamide; nitriles, such as acetonitrile, and sulfones, such as dimethylsulfone.

Moreover, it is necessary that the reaction according to the invention be carried out in the presence of at least one strong base. For the purposes of the present invention, by strong bases are meant all organic bases which have a pK, less than 8.7, preferably less than 3.3. These include, in the main, aliphatic amines such as triethylamine, trimethylamine, or heterocyclic tertiary amines such as a-picoline, lutidines, and the like.

The reaction temperatures can be varied within a wide range. In general, the reaction is carried out at to 50 0., preferably to 30 C.

When carrying out the process according to the invention, the Starting materials and the strong base are normally used in approximately equimolar amounts. In the case where R in the general formula stands for the group of the Formula II, approximately 2.4 moles of imidazole derivative are normally reacted with each mole of the compound of the Formula IV. In this case, approximately 2 moles of strong base are normally necessary. The working up of the reaction mixture obtained may take place in customary manner.

The acylimidazoles of the invention can be used as intermediates for the preparation of crop protection agents, such as fungicides and growth regulators. Thus, the 2-acylimidazoles, with physiologically compatible acids, such as hydrohalogen acids, phosphoric acids, sulphonic acids, aliphatic mono, diand hydroxy-carboxylic acids, form salts which are effective against apple scab (Fusicladium dendriticum). Further, the acylimidazolesof the present invention can be used for the preparation of compounds which are effective against Protozoa. (compare the German patent application P 19 11 646.2, filed Mar. 7, 1969.)

The preparation of the new compounds of the present invention are illustrated, without limitation, by the following examples.

- EXAMPLE 1 Benzoyl-l-methylimidazole 4' 82 g. (l -mole) of l-methylimidazole are dissolveduin 1000 ml. acetonitrile and, after addition of 141 g. (1 mole) of benzoyl chloride and 101 g. (1 mole) of triethylamine at 0, the mixture is stirred at 20 C. for 10 hours. The triethyl ammonium chloride formed is removed by filtration, the filtrate is 'heatedto evaporate the solvent, the residue is dissolved in benzene, the benzene' solution is washed-salt-free, dried and evaporated. The resulting oil is distilled in a high vacuum. B1B. 136 145 C./0.3 mm. Hg, 1.6138, M.P. 50 C-.-"Y ield 108 g.

EXAMPLE 2'- 2-p-chlorobenzoyl- 1 -methylimidazole C Ha EXAMPLE 3 Ki o-{ i I 2-o-fiuorobenzoyl-l-methylimidazole is ogously with Example 2, M.P. C.

EXAMPLE 4 2-p-nitrobenzoyl-l methylimidazole KLWQM, 7

prepared anal- 41 g. (0.5 mole) of l-methylimidazole are dissolved in 800 ml. of acetonitrile, 92.8 g. (0.5 mole) of p-nitrobenzoyl chloride are added, and 50.5 g. (0.5 mole)'-"of triethylamine are added dropwise at 0 C. After 20'hours the resultant crystal slurry is suction filtered and'wa's'hed salt free and dried, M.P. 168 C.

EXAMPLE 5 2-ethoxycarbonyll-methylimidazole 82 g. of l-methylimidazole are dissolved in 600 ml. of acetonitrile, 108.5 g. of chloroformic acid ethyl ester are added, with cooling, and 101 g. of triethylamine are added dropwise at 0 C. After the ,triethylammonium chloride has been filtered 01f, the solvent is evaporated, the residue is taken up in methylene chloridearid the solvent is evaporated. The crude productis purifiedby distillation in a high vacuum. HP. 10

C./0.5 mm. Hg, 41 g.; n 1.5086, M.P. 50 C. i

TABL EContinued Example No. Physical properties (A718) 2-(2 -iurylcarbony l)-1-n propylimldazol B.P. 135 C./0.1 mm. P

(A49) '2-(2-lurylearbonyl)-l-inethallylimidazole B.P. 130 C./0.l mm. i t z .1 p r t g. (A-) 2-(2-cl1lor0benzoyl)-1-benzylirnidazolo.; 13.5. 180 C./0.07 mm. (A-21) 2-(4'-chlorobenzoyl)-1-benzoylimldazole M.P. 82 C. (A-22) 2-( U-ch10robenzoyD-l-ethylimidazole Big. 180 C./0.2 mm. (A-23) 2-(4-nltrobenzoyl)-l-ethylimidazole (A-24). 2-(4'-nitrobenzoyl)-1-n-propylimidazole (A-25). 2-(4-chlorobenzoyl)-1-n-pr0py1imidazolo. H (A-26) 2-(2-iurylcarbonyl)-1-etliylimldaz0le B.HP. 155 O./l.5 mm. f

(A-27)...-..... 2-(2'-chlorbenz0yl)-1-n-propylimidazole Big. 155 C./0.05 mm.

g. (A-28). 2-(2-ch1orobenzoyl)-1-ethylimidazole (A-29)- 2-(2-furylcarbonyl)-1-methylbenzimidazo .P. o (A-30).. 2-trichloracetyl-l-allylimidazole .P. 68 C. (A-31) 2-trichloracetyl-l-ethy .P. 61 C. (ii-32) 2-trlch10racetyl-l-methnllylimidazole M.P. 58 C. (A-33) 2-trichloracetyl-1-n-propylimidazole M1. 45 C.

In a similar manner, there are also obtained:

EXAMPLE 40 EECOQ-CLHCI The compound according to the invention prepared according to Example 12 is dissolved in ether. Hydrogen chloride is then introduced at room temperature until saturation. After cooling to about 0 C., the hydrochloride precipitates; it is suction filtered and dried over phosphorus pentoxide. The melting point of the salt is 80 C.

EXAMPLE 41 The hydrochloride is obtained from the compound prepared according to Example 13 and hydrogen chloride; the melting point is 190 C.

EXAMPLE 42 Application example: Fusicladium test/in vitro The salts of the novel acylimidazoles according to the invention possess fungicidal properties, as a test on F usicladium dentriticum (apple scab causative organism) shows. p I

The active compounds are applied in aqueous suspension of 0.0005% concentration; the germination of the spores of Fusicladium dentriticum is then observed and evaluated in accordance with the following scale:

0--denotes no infection a I I--denotes very slight infection II-denotes slight infection IIIdenotes moderate infection IV-denotes strong infection V--denotes infection as in the case of the untreated control (no effect) The other compounds of the present invention possess similar utility as well as being useful for further synthesis.

It will be appreciated that the instant specification and examples are set forth by way of illustration and not limitation, and that various modifications and changes may be made without departing from the spirit and scope of the present invention.

What we claim is:

1. A process for the production of an acylimidazole of the formula llm i R (1) in Which R is tertiary alkyl of 4-6 carbon atoms; or chloro-, fluoro-, bromo-, nitroor amino-alkyl of 1-6 carbon atoms; or lower alkoxy, lower alkylthio or di-lower alkylamino; or phenoxy or phenylthio; or phenyl, biphenyl, naphthyl, cycloalkyl of 5 to 6 carbon atoms, cycloalkenyl of 5 to 6 carbon atoms, pyridyl, pyrazolyl, oxazolyl, thiadiazolyl or furyl each optionally substituted by one or two members selected from the group consisting of chlorine, fluorine, bromine, nitro, lower alkyl or lower alkoxy; or a radical of the formula x -N 1 II Y \N/ A 1 1 (II) in which A is a direct bond, -CO--, or COCH or TI Y J is reacted at a temperature of about to 50 C. with a compound of the formula the COCl radical of which is attached directly to a carbon atom.

2. A process according to claim 1 in which the polar diluent in an inert organic solvent which has a dielectric constant of at least 20.7.

3. A process according to claim 2 in which the polar diluent is an amide, nitrile or sulphone.

10 4. A process according to claim 1 in which the strong base is an organic base with a pK less than 3.3.

References Cited UNITED STATES PATENTS 3,113,948 12/ 1963 Zellner 260-3092 3,320,273 5/1967 Kollonitsch 260309.2 3,325,507 6/1967 Kollom'tsch 260309 3,378,552 4/1968 Henry 260-309 3,515,728 6/1970 Henry et al. 260309 3,590,047 6/1971 Shen et al. 260309.2

OTHER REFERENCES Parker: In: Raphael et al. Advances in Organic Chemistry, vol. 5, pp. 2-3 relied on (1965).

Aryuzina et al.: Chem. Abst., vol. 66, No. 949522 (1967).

Aryuzina et al.: Chem. Abst., vol. 69, No. 96572m (1968).

Boyer et al.: J. Amer. Chem. Soc., vol. 74, pp. 4506-8 (1952).

Kurihara 'et al.: Chem. Abst., vol. 55, columns 14439- 40 (1961).

Takahashi et al.: Chem. Pharm. Bull., vol. 12, pp. 282-91 (1964).

Tertov et al.: Chem. Abst., vol. 60, column 8020 (1964).

Tertov et al.: Chem. Abst., vol. 69, No. 59158k (1968).

Hofmann: Imidazoles and Its Derivatives Part I, p. 127, New York, Interscience, 1953.

NATALIE TROUSOF, Primary Examiner US. Cl. X.R.

260-2949, 296 B, 302 D, 307 R, 309, 309.2, 310 R; 424263, 270, 272, 273 

